NIH Public Access: Food-Induced Anaphylaxis

NIH Public Access
Author Manuscript
Immunol Allergy Clin North Am. Author manuscript; available in PMC 2013 February 01.
Published in final edited form as:
NIH-PA Author Manuscript
Immunol Allergy Clin North Am. 2012 February ; 32(1): 165–195. doi:10.1016/j.iac.2011.10.002.
Food-Induced Anaphylaxis
Antonella Cianferoni, MD, PhDa,* and Antonella Muraro, MD, PhDb
aAllergy and Immunology Division, The Children’s Hospital of Philadelphia, University of
Pennsylvania, ARC 1216H, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
bDepartment of Pediatrics, Food Allergy Referral Center, Padua General University Hospital, Via
Giustiniani 3, 35128 Padua, Italy
Keywords
Anaphylaxis; Food; Allergy
DEFINITION
Food-induced anaphylaxis (FIA) is a serious allergic reaction that may cause death rapidly
in otherwise healthy individuals. There is no universal agreement on its definition or criteria
for diagnosis.1 In 2006 an international task force on anaphylaxis recommended a new
working clinical definition of anaphylaxis, which tried to address such issues (Box 1).2
Box 1
Clinical criteria for the diagnosis of anaphylaxis
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the
skin, mucosal tissue, or both (eg, generalized hives, itch or flushing, swollen
lips, tongue, or uvula, rhinorrhea, conjunctivitis). And at least one of the
following:
a. Respiratory compromise (eg, dyspnea, bronchospasm, stridor, hypoxia)
b. Cardiovascular compromise (eg, hypotension, collapse)
2. Two or more of the following that occur rapidly after exposure to a likely
allergen for that patient (minutes to several hours):
a. Involvement of the skin or mucosal tissue (eg, generalized hives, itch,
flushing, swelling)
b. Respiratory compromise (eg, dyspnea, bronchospasm, stridor, hypoxia)
c. Cardiovascular compromise (eg, hypotension, collapse)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain,
vomiting)
© 2012 Elsevier Inc. All rights reserved.

*
Corresponding author: cianferonia@email.chop.edu.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for
Research Resources or the National Institutes of Health.
Conflict of interest: The authors have no financial conflicts of interest to disclose.
Cianferoni and Muraro Page 2
3. Hypotension after exposure to known allergen for that patient (minutes to

several hours)
Hypotension for children is defined as systolic blood pressure <70 mm Hg from 1 month
to 1 year [<70 mm Hg + (2 × age)] from 1 to 10 years, and <90 mm Hg from 11 to 17

years.
Data from Muraro A, Roberts G, Clark A, et al. The management of anaphylaxis in
childhood: position paper of the European Academy of Allergology and Clinical
Immunology. Allergy 2007;62(8):857–71.
Based on this latest recommendation,1,3 FIA is diagnosed when

1. Two or more of the following symptoms occur rapidly and acutely after exposure
to a likely allergen and:
• Involvement of the skin or mucosal tissue, respiratory compromise,
cardiovascular compromise, persistent gastrointestinal symptoms
2. Hypotension after exposure to known allergen for that patient.
EPIDEMIOLOGY
The epidemiology of FIA has been difficult to quantify, with estimates varying widely2;
however, there is general agreement that hospital admissions for FIA have more than
doubled in the last decade.4
Epidemiologic challenges in determining the burden of FIA has been reviewed5 and are
listed in Box 2.
Box 2
Epidemiologic challenges in determining the burden of food-induced
anaphylaxis
1. Lack of universal consensus on consistent definition to identify anaphylaxis
(especially for studies published before the new 2006 guidelines2)
2. Difficulty in distinguishing anaphylaxis from other disorders
3. Selection bias based on hospital presentation
4. Use of different measures of disease occurrence to estimate disease burden
(such as prevalence and incidence)
5. Limited ability of International Classification of Diseases (ICD) 995.6 code

(“anaphylactic shock due to adverse food reaction”) to identify specific allergic
reactions in the emergency department, as it is not realistic to expect physicians
(or health statistics) to code anaphylactic reactions defined as multisystem organ
involvement, but not shock, with codes specifically including shock
Bearing in mind the limitation cited in Box 2, it is estimated that the incidence of:
• Fatal reaction due to FIA is 1 in 800,000 per year in children and 1 in 4 million for
adults
• Nonfatal reaction due to FIA is reported to be between 0.5 and 16 cases per
100,000 person-years.6–9
These numbers may underestimate the actual burden of anaphylaxis or risk of anaphylaxis in
the general population. Indeed it is estimated that 0.1% to 5% of children have a prescription
for epinephrine,10,11 and that in the United States the direct and indirect cost of
hospitalization, emergency room visits, epinephrine prescription, and ambulance transport

related to FIA is more than $40 million per year, with about 75% of these costs attributable
to pediatric patients.12
Peanut/tree nuts anaphylaxis is estimated to have a prevalence of 0.25% to 0.95% in the

United Kingdom and United States pediatric populations, and appears to be on the increase
in the last decade.13–15 This statistic mirrors the increased prevalence of peanut and tree nut
allergy reported in United States children. Peanut allergy recently has been found to be 2.6%
in the general population and 22.6% among children sensitized to peanut.16 In general, the
prevalence of adverse reactions to foods is higher in children than in adults; however,
allergy to nuts is an important problem in adulthood, the prevalence of allergy to nuts being
higher in adults (1.6%) than in children (0.6%).14 As allergy to nuts persists over the years,
these data could reflect a cumulative effect in adults because peanut and tree nut allergy
seems to develop early in life, with most affected children in the United States and the
United Kingdom developing symptoms before the age of 2 years.17,18
Shellfish anaphylaxis has a prevalence of 0.44% in the United States.19 The consumption of
seafood has risen by approximately 50% over the last 40 years, both in the United States and
elsewhere,20 corresponding to an increase in the incidence of seafood allergy over the same
period, with significantly lower rates in children compared with adults19,21 as happens for
tree nut and peanut allergy.
TRIGGERS OF FIA
Food is one of the most common causes of anaphylaxis, with most surveys indicating that
food-induced reactions account for 30% to 50% of anaphylaxis cases in North America,
Europe, Asia, and Australia,4,6,7,9,12,22 and for up to 81% of anaphylaxis cases in
children.23,24
Although a wide range of foods has been reported as the cause of FIA, the most commonly
implicated foods worldwide are peanut, tree nuts, milk, egg, sesame seeds, fish, and
shellfish2,3,5,6,9,25,26 in both adults and children (Table 1). However, the individual food
allergy varies by culture and population. For example, peanut allergy is one of the most
common causes of FIA in the United States, United Kingdom, and Australia, but is rare in
Italy and Spain (where consumption of peanut is significantly lower than in the United
States) or China (where peanut consumption is similar to that in the United
States).5,6,25,27–30
Even if prior exposure is necessary for the development of sensitization, 72% patients with
peanut and/or tree nut allergy reported symptoms during their first known exposure.31 These
patients may have had previous unknown exposures through breast milk, contamination with
other foods, or use of topical products containing food oils (eg, peanut).32
Reports of anaphylaxis in exclusively breast-fed babies due to passage of food allergens

from the mother to the infant are extremely rare,33,34 and there are no reports in the
literature of fatal FIA in exclusively breast-fed infants.
The spectrum of foods responsible for causing anaphylaxis appears to be broadening, to

include fruits and other foods not previously commonly associated with anaphylaxis.
• Asero and colleagues29 recently reported on a series of 1110 adolescent and adult
Italian patients (mean age 31 years, range 12–79 years) diagnosed with food allergy
based on history of reaction in the presence of positive skin prick test (SPT) or
elevated food-specific serum IgE. Anaphylaxis was reported by 5% of food-allergic

individuals, with the most common cause being lipid transfer protein (LTP). LTP is
a widely cross-reacting plant pan-allergen. Offending food for LTP-allergic
patients was most often peach, but included also other members of the Rosaceae
family of fruits (apple, pear, cherry, plum, apricot, medlar, almond, strawberry),
tree nuts, corn, rice, beer, tomato, spelt, pineapple, and grape.35–37
• Recently there have been several case reports of anaphylaxis resulting from
ingestion of lupin flour, which is being increasingly used in bakery products in
France and Mediterranean countries.38,39
• Moreover, some newly described food allergens appear to cause specific clinical
subtypes of anaphylaxis.
– Water-insoluble omega-5-gliadin (Tri a 19) has been identified as a major
allergen in Finnish subjects with food-dependent exercise-induced
anaphylaxis (FDEIA), with in vitro and in vivo cross-reactivity to rye
allergens and barley allergens, but not oat allergens.40,41
– A carbohydrate nonprotein food allergen, galactose-α-1,3-galactose (α-
gal), is capable of eliciting delayed systemic symptoms of anaphylaxis,

angioedema, or urticaria associated with eating beef, pork, or lamb 3 to 6
hours earlier, and appears to be more common in middle-aged men living
in Virginia, North Carolina, Tennessee, Arkansas, and Missouri, as well as
in Australia. Given the peculiar geographic distribution and the fact that
more than 80% of the patients reported being bitten by ticks, researchers
were able to provide evidence that tick (Amblyomma americanum or
Ixodes holocyclus) bites are a (possibly singular) cause of IgE-mediated
sensitization to α-gal in these areas of the United States and
Australia.42–44
Peanut/Tree Nut Anaphylaxis

Peanut and tree nuts are overwhelmingly and disproportionately represented in case series of
severe and fatal outcomes, severe allergic reaction, and visits to the emergency department
for food anaphylaxis, particularly in United States, Germany, Australia, and the United
Kingdom (see Table 1),4,5,45–48 and allergy to peanut and tree nuts is becoming a significant
health problem in many parts of the world.49 Large surveys indicate that in comparison with
other foods, allergic reactions to nuts seem to be particularly severe, with multisystemic or
respiratory symptoms in up to 81% of the cases. Some studies indicate that severity of
coexisting atopic diseases may be a risk factor in the development of life-threatening allergic
reactions to peanut and tree nuts.50
Recent advances in allergy sequencing and the availability of platforms for IgE specific for
single epitopes of the single allergens have increased our understanding of which epitopes
are more important in the triggering of an allergic reaction. Major allergens described for
peanut and tree nuts are listed in Tables 2a and 2b. Serologic studies have shown that the
diversity of IgE recognition of peanut proteins is associated more with clinical outcome than
with recognition of individual allergens.51 However, some studies suggest having IgE
specific to Ara h 2 is associated with more severe (mostly respiratory) symptoms, whereas
Ara h 8, a Bet v 1 cross-reactive allergen, more often causes less severe reaction such as oral
syndrome.52 Different food processing methods used in different countries may be
responsible for increased or decreased peanut allergenicity, and consequently peanut allergy
prevalence in countries with similar consumption such as China and the United States.
Indeed the dry-roasting process (150°C) used in United States enhances the allergenicity of
Ara h 1, 2, and 3, whereas boiling (100°C) or frying (120°C) used in China reduces the
allergenic properties of these molecules.30
One of the most common reported tree nut allergies is that of the cashew. One-third of the
patients reacting to cashew nuts are also allergic to pistachios, which belongs to the same
botanic family (Table 3). Severe allergic reactions to hazelnuts, including systemic
anaphylaxis, have also been described in patients sensitized to Cor a 8 (LTP) and Cor a 9
(11S globulin).53 In United States children the most common tree nut allergies are walnut,
almond, and pecan.31 Allergic reactions to other nuts such as Brazil nuts, pistachios,
macadamia nuts, pine nuts, and coconuts are less common triggers of FIA and have been
reported anecdotally.49 Chestnut allergy is generally observed in the context of latex-fruit
syndrome.54
Assessment of cross-reactivity among tree nuts is complicated by shared allergens among

the nuts and between nuts and other plant-derived foods and pollens. If skin test reactivity is
a result of cross-reactivity to pollens, food reactions are typically absent or mild (ie, oral
allergy syndrome) (see Tables 2a and 2b).49 Some nut allergens may be homologous and
cause reactions (eg, in pistachio and cashew), whereas others may be homologous but rarely
elicit clinical cross-reactivity (eg, proteins in coconut and walnut). Clinical relevant cross-
reactivity is estimated to be around 30% to 40%; however, fatal reactions have been
described from a first exposure to a nut in patients allergic to other nuts.55 Hence,
considering the potential severity of the allergy and issues with accurate identification of
specific nuts in prepared foods, very often a total elimination of the nut family (perhaps with
the exception of previously tolerated nuts eaten in isolation) is suggested by most
clinicians.55 Cross-reactions to seeds, such as sesame, mustard, and poppy, have also been
reported.56–64
Cosensitization to allergenic foods, such as peanut, tree nuts, and seeds (sesame, poppy, and
mustard) is common, although clinically significant cross-reacting proteins have not yet
been described. Coallergy to peanut and tree nut has been reported as between 23% and 50%
in referral populations of atopic patients and 2.5% in unselected populations.56
Seafood
Seafood is a common cause of anaphylaxis, and fatal events have been reported (see Table
1), with a rate of anaphylaxis among sensitized patients of about 20%.20 Shellfish are a
nontaxonomic group that includes crustaceans and mollusks, which are invertebrates, unlike
fish (see Table 3). The major shellfish allergen has been identified as tropomyosin, an
essential protein in muscle contraction, which is a pan-allergen responsible for in vivo and in
vitro cross-reactivity between crustaceans (shrimp, crab, crawfish, lobster), insects
(cockroaches), arachnids (house dust mites), and different classes of mollusks (Table 2c).65
The situation with fish is less certain, with reports of both polysensitization to multiple
species (50%–92% of individuals) and monosensitization to a single fish type. The major
allergens responsible for cross-reactivity among noncrustacean fish are the muscular
parvalbumins (see Table 2c), pan-allergens resistant to thermal and enzymatic
degradation.65 Canned fish, which is cooked for up to 7 hours under pressure, may be less
allergenic; however, anaphylaxis related to canned fish has been reported, so this food is not
safe for patients with fish-induced anaphylaxis.20
Cross-reactivity between crustaceans and fish has been not reported, so affected individuals
are usually advised to avoid either fish or crustaceans; however, up to 50% of individuals
may be sensitive to both shellfish and fish.20
Despite a generalized belief within the medical community, allergies to shellfish do not
increase the risk of reaction to intravenous contrast.66
Milk, Egg, and Soy

In the pediatric population, milk and egg allergy are a frequent cause of anaphylactic
reactions.67,68
Milk is also the third most common food responsible for fatal or near-fatal food-induced
anaphylactic reactions (8%–15% cases),67–69 and appears to be globally one of the most
common causes of anaphylaxis in young children (see Table 1).28,48,70,71 Acute (IgE-
mediated) reactions to milk are caused by various milk allergens mainly belonging to the
family of caseins and whey proteins (see Table 2a).72,73 Cooking diminishes the
allergenicity of whey proteins, presumably by denaturation of heat-labile proteins, resulting
in loss of conformational epitopes. Children reactive to extensively heated milk (but not
egg) are at higher risk for systemic reactions treated with epinephrine than those children
tolerant to heated milk but reactive to unheated milk, suggesting a possible correlation
between sensitivity toward different epitopes in the allergens and severity of reaction.74
Indeed the importance of sequential epitope recognition in the persistence of cow’s milk
allergy has been highlighted in several studies.75–79 Cooking-induced allergen denaturation
may explain why many patients allergic to cow’s milk tolerate extensively heated milk.74,80
Similarly, yogurt cultures, which ferment and acidify milk, contain less intact whey protein,
therefore individuals with cow’s milk allergy exclusively sensitized to whey proteins may
tolerate yogurt-based dairy products.81 However, in children with near-fatal anaphylaxis it is
prudent to avoid all forms of milk even in minor quantities. Mammals that are
phylogenetically related have quite similar milk protein expression, hence no mammalian
milk (ie, goat, donkey, and so forth) is safe for children with anaphylaxis to milk.81
Fatal reactions to egg are rare, but have been reported.22 Food-dependent, exercise-induced
anaphylaxis with egg as the trigger has also been reported.82 Five major allergenic proteins
from the egg of the domestic chicken (Gallus domesticus) have been identified, and are
designated Gal d 1 to Gal d 5. Most of the allergenic egg proteins are found in egg white.
Although ovalbumin (OVA) is the most abundant protein in hen’s egg white, ovomucoid
(OVM) has been shown to be the dominant allergen in egg. Egg-specific IgE molecules that
identify sequential or conformational epitopes of OVM and OVA can distinguish different
clinical phenotypes of egg allergy. It has been shown that patients with egg allergy with IgE
antibodies reacting against sequential epitopes tend to have persistent allergy, whereas those
with IgE antibodies primarily to conformational epitopes tend to have transient allergy.
Studies have shown that ingestion of raw or undercooked egg may trigger more severe
clinical reactions than well-cooked egg.83 Manufactured food products often contain trace
amounts of egg lecithin as emulsifiers, but ingestion of trace amounts of egg lecithin is
probably insufficient to elicit allergic reactions.84
Although severe soy allergy reactions have been reported, they are quite rare and far less
common than milk allergy (see Table 1).85,86 The specificity of soy allergens is variable and
complex. As many as 28 different soy proteins have been recognized as being allergenic;
however, only a few are considered major allergens. Gly m 5 and Gly m 6 account for about
30% and 40% of the total seed proteins, respectively, and have been shown to be a potential
indicator for severe allergic reactions to soy (see Table 2a).87 Most individuals with
anaphylaxis induced by cow’s milk allergy tolerate soy if such patients have no IgE to soy.81
Clinical cross-reactivity between peanut and soy, both legumes, is extremely rare despite the
high degree of cross-sensitization, and is estimated to be less than 7%.37,88,89
RISK FACTORS
The major risk factor for FIA appears to be food allergy. Indeed the majority of patients with
fatal or near-fatal FIA are known to be allergic to the food that caused the anaphylactic
reaction.2,28,67,90 The severity of previous allergic reaction is not predictive of the severity
of future allergic reaction, as the experience accumulated with food challenge and reports on
fatal FIA seems to indicate.68,91 Therefore it is not surprising that recent National Institutes
of Health (NIH) guidelines for the management of food allergy encourage clinicians to
consider prescribing an epinephrine autoinjector for all patients with documented IgE-
mediated food allergy reactions, because it is impossible to predict the severity of any
subsequent reactions with accuracy.45 The group at highest risk of FIA are young male
children, while among adults women are at higher risk. Overall the group at highest risk for
fatal anaphylaxis is young adults.23,28,29,67,71,92 Among patients with food allergy, those at
highest risk45,67,68,93 are those with a history positive anaphylaxis, those with asthma (risk
increases with the severity of asthma),46,92 those with allergy to peanut, tree nuts, and
shellfish, and adolescents.
Several factors can contribute to lower the “threshold” for anaphylaxis, possibly by
increasing the allergen uptake (ie, exercise, alcohol, drugs that increase gastric pH) or by
enhancing the inflammatory response (ie, febrile illness, asthma exacerbation, or
nonsteroidal anti-inflammatory drug use); hence the unpredictability of future reaction.94
Higher income, living in an area with low sun exposure, and possible low level of vitamin D
may predispose individuals to develop anaphylaxis.95,96
PATHOGENESIS
FIA is a typical IgE-mediated allergic reaction, being immediate, reproducible, and readily
diagnosed by detection of food-specific IgE. FIA is initiated by the engagement of allergen-
specific IgE antibody with its high-affinity receptor (FcεRI) that is expressed on mast cells
and basophils. When a specific antigen binds the IgE linked to the FcεRI it determines a
receptor cross-link and consequent release of preformed mediators (histamine, tryptase,
carboxypeptidase A, proteoglycans, and some cytokines) and newly synthesized ones
(leukotrienes, bradykinins, cytokines including tumor necrosis factor α, and platelet-
activating factor [PAF]).97,98 Ultimately, these mediators cause the characteristic clinical
features of anaphylaxis, including vasodilation, angioedema, bronchoconstriction, and
increased mucus production (Table 4).99–101
Even if initially it was thought that mast cells were the principal effector cells in IgE-
mediated acute reaction, further studies have shown that basophils also play a major role in
acute food allergy symptoms. Indeed patients with food allergy have higher rates of
spontaneous release of histamine from basophils, which normalizes after the offending food
has been removed from the diet. Furthermore, normal serum tryptase levels (a specific
marker of mast cell activation) in patients with FIA have been reported, suggesting an
involvement of histamine release from tryptase-negative cells such as basophils. Moreover,
in a peanut anaphylaxis animal model the combined deficiency of mast cells and
phagocytes, but not mast cells and basophils, averted nearly all clinical and physiologic
signs of anaphylaxis, suggesting that other cells of the innate immune system may play a
role in anaphylaxis.102
Histamine is one of the major preformed mediators released by mast cells and basophils, and
can induce most of the characteristics of anaphylaxis when administered intravenously to
humans and laboratory animals (see Table 4).99 However, even the strongest inhibitors of
histamines are not sufficient to block or reverse anaphylaxis, suggesting other mechanism
may also be involved.103,104 In the past few years, PAF has emerged as a major player in the
propagation of anaphylaxis. PAF is a preformed mediator released by mast cells, monocytes,
and tissue macrophages during anaphylaxis, and is capable of activating mast cells in the
lung and peripheral blood but not in the skin.105 Higher levels of PAF and lower levels of its
metabolizing enzyme (PAF acetylhydrolase) have been found by Vadas and
colleagues106,107 to correlate with the severity of the anaphylactic attack. Recently, Arias
and colleagues108 showed that a molecule that blocks PAF prevents severe anaphylactic
reactions and, when combined with antihistamines, abolishes nearly all signs of anaphylaxis.
In a mouse model of peanut anaphylaxis it has been shown that peanut may contribute to
induce anaphylactic shock by causing activation of the complement cascade and relative
production of C3a, which stimulates macrophages, basophils, and mast cells to produce PAF
and histamine.109
Patients with the lowest serum angiotensin-converting enzyme concentrations were also
more likely to develop life-threatening pharyngeal edema in peanut-induced FIA, suggesting
that this complication may be partly mediated by bradykinins.50
The intrinsic properties of the food allergens may contribute to whether the allergen favors
allergic immune responses. Indeed, relatively few foods (egg, milk, peanut, tree nuts, fish,
shellfish) account for most of the allergic reactions.110 Characteristics common to major
food allergens are that they are water-soluble glycoproteins, are 10 to 70 kDa in size, and are
relatively stable to heat, acid, and proteases. To elicit a sustained immune response, the
immunogenic molecule should ideally stimulate both T and B cells. The portion of the
immunogenic molecule that binds specifically with membrane receptors on T or B cells is
called an epitope, which can be sequential or conformational. Sequential epitopes are
determined by contiguous amino acids, whereas conformational epitopes contain amino
acids from different regions of the protein that are in close proximity because of the folding
of the protein. Conformational epitopes can be destroyed with heating or partial hydrolysis,
which alters the tertiary structure of the protein, hence they are less stable, heat/enzyme
labile, and often cause less severe reactions especially when cooked.83
In addition, the presence of immunostimulatory factors in the food may also contribute to
such sensitization. For example, the major glycoprotein allergen from peanut, Ara h 1, is not
only very stable and resistant to heat-digestive enzyme degradation but also acts as a Th2
adjuvant, due to the expression of a glycan adduct.111,112
DIAGNOSIS
Clinical
Anaphylaxis remains first and foremost a clinical diagnosis. A good history remains the
most powerful tool that physicians have to confirm both a history of FIA and the food
trigger. Indeed anaphylaxis occurs soon after food ingestion (see Box 1), and patients
themselves often notice the relationship with the eliciting food. However, the patient’s own
perceptions and knowledge may influence history, so the physician has to ensure correct
compilation of the history. Thus a systematic review of all patient’s symptoms, patient’s
diet, and the last meal before the reaction are a highly useful first step. As described in Box
1, anaphylaxis is characterized by a combination of cutaneous, respiratory, cardiovascular,
and gastrointestinal factors. The presence of all of these symptoms need to be asked of
patients and parents, because patients may only initially remember or mention the more
severe or obvious ones. Reactions of skin and mucosal involvement such as urticaria,
angioedema, itch, rhinorrhea, and conjunctivitis present in a high percentage (70%–98%) of
patients, especially in young children.35,48,56,113 However, anaphylaxis without skin or
mucosal involvement have been described, and relying solely on skin manifestation may
delay the diagnosis and could be fatal for the patient.68 Perhaps because the gastrointestinal
mucosa is the location of exposure in FIA, immediate gastrointestinal hypersensitivity is
commonly seen as a manifestation of anaphylaxis.27,90 Abdominal pain and vomiting is
common especially in children, and can be the primary manifestation of anaphylaxis with
only minimal involvement of other organs.23,48,71 Cardiovascular symptoms can rapidly
cause the death of the patient, and need to be recognized at an early stage. Close monitoring
of blood pressure with the correct cuff size for age is essential in all patients with suspected
or ongoing anaphylaxis. However, cardiovascular symptoms are much less common in FIA
compared with other types of anaphylaxis, and are rarely found in isolation from respiratory
arrest. In infant and preschool children, reactions tend to be less likely to involve the
cardiovascular system.23,48,71 Respiratory manifestation such edema of the glottis and
asthma are the primary cause of death in patients with FIA and need to be treated
aggressively, especially in asthmatic patients.67–69
The time from ingestion of food to the onset of FIA symptoms is usually on the order of
minutes, and almost never occurs after 2 hours from ingestion of the triggering foods.91 In
small children timing can help to differentiate between anaphylaxis and food protein–
induced enterocolitis (FPIES), a non-IgE–mediated food allergy that typically begins later
than 1.5 hours after ingestion.
Additional elements of clinical history can be helpful. Knowing the quantity necessary to
trigger a reaction is helpful in evaluating risk of anaphylaxis for trace amounts of foods and
the severity of anaphylaxis.
One area of considerable controversy in the literature is the true frequency of biphasic
reactions during anaphylaxis. In a biphasic reaction, symptoms of the initial reaction resolve
but are followed by new symptoms without any further allergen exposure, and are never
more severe than the first manifestation. The true incidence of biphasic reaction and
prevention measures is not known. Published reports suggest that biphasic reactions occur in
5% to 28% of anaphylaxis cases, with the highest incidence in FIA. However, in children
undergoing oral food challenge (OFC) reactions are extremely rare.85,114 There is also
conflicting evidence about whether administration of steroid or epinephrine can prevent a
biphasic reaction.114
When history is not convincing, other diseases that may mimic FIA have to be considered
(Box 3), and laboratory evaluation in the acute phase may be important. Especially
important in the differential diagnosis of FIA are the restaurant syndromes and toxic
reactions due to fish intake (see Box 3 and Table 5).
Box 3
Differential diagnosis of food-induced anaphylaxis
1. Vasovagal reactions
2. Non-IgE–mediated food allergy
a. FPIES
3. “Flush” syndrome
a. Carcinoid
b. Postmenopausal
c. Chlorpropamide alcohol
d. Medullary and thyroid carcinoma

e. Autonomic epilepsy
4. “Restaurant syndromes”
a. Monosodium glutamate
b. Sulfites
c. Scombroid
5. Other shock
a. Hemorrhagic
b. Cardiac
c. Endotoxic
d. Monoclonal gammopathy (paroxysmal hyperpermeability)
6. Syndromes with excessive endogenous production of histamine
a. Mastocytosis
b. Urticaria pigmentosa
c. Basophil leukemia
d. Promyelocytic acute leukemia
e. Hydatid cyst
7. Nonorganic syndromes
a. Panic attack
b. Munchausen
c. Vocal cord dysfunction
d. Hysteric bolus
8. Miscellaneous
a. Hereditary angioedema
b. Anaphylaxis due to progesterone

c. Urticaria vasculitis
d. Pheochromocytoma
e. Hyper-IgE syndrome
f. Neurologic diseases (seizures, stroke)
g. Pseudoanaphylaxis
h. Red man syndrome (vancomycin)
Laboratory Studies
At present, there is no laboratory test that reliably confirms cases of FIA. Indeed histamine
and tryptase serum levels are less helpful in FIA than in other types of anaphylaxis. Serum
histamine levels are elevated only for 30 to 60 minutes after the onset of reaction, so they
are very rarely measured. The most commonly assessed mediator in clinical practice is
tryptase, whose blood levels peak 1.5 hours after the onset of symptoms and are measurable
for up to 5 hours. However, in FIA tryptase is less commonly elevated than in other types of
anaphylaxis.114 Other laboratory tests may be important in ruling out nonanaphylactic
causes of symptoms, as shown in Box 4.
Box 4
Examinations in cases of nonconvincing anaphylaxis
Blood Tests
Serum histamine (within 1 hour)
Tryptase (within 5 hours)
CH50, C1 esterase → Hereditary angioedema
IgA, IgM, IgG immunoelectrophoresis → monoclonal gammopathy
Cardiac enzymes → cardiac ischemia?

Serotonin → carcinoid syndrome?
Urine
Histamine
5-Indoleacetic acid, vanillylmandelic acid, catecholamines → carcinoid syndrome,
pheochromocytoma
Other
Blood pressure monitoring
Electrocardiogram
Echocardiogram
Chest radiograph
Liver ultrasound examination
Parasites in feces
Diagnosis of the food allergen that caused anaphylaxis is the most important step in
preventing future reaction; hence referral to an allergist is essential for the appropriate
workup. Food allergy diagnosis is made primarily on the history and on a few tests done to
confirm the history. An SPT examines for the presence of food protein–specific IgEs, having
a positive predictive accuracy of about 50% that the patient will react to the tested food. The
larger the size of wheal on SPT, the more accurate is such a predictive value; however,
negative predictive values are in excess of 95%. Furthermore, the age of the patient,
previous exposure reactions to the food, and the type of food change the predictive value for
a wheal size. An alternative method to detect food protein–specific IgE is by in vitro
methods (FEIA-CAP or “RAST test”). Some clinicians may prefer to use in vitro testing
when there is persistent dermatographism (rare) in the few weeks following an anaphylactic
shock (ie, mast cell refractory period), severe eczema, or when the patient is on
antihistamines. Indeed in all these conditions skin tests may not be reliable. Similar to SPT,
a cutoff value can be developed for predicting 50% to 95% of who will react to foods. SPT
or levels of specific IgE give only an indication of the likelihood of clinical reactivity;
however, individual results do not provide prognostic information or distinguish between

likelihood of mild or severe reaction.51,76,98,114,115 Recently, peptide microarrays have been
developed for large-scale epitope mapping, with small quantities of serum allowing large-
scale study to compare levels of IgE and their affinity toward specific epitopes of different
allergens.51,72,73,116–122 So far no single informative epitope that reliably distinguishes
between the different phenotypes of milk, egg, or peanut allergy has been identified because
of the heterogeneity of epitopes recognized by subjects within the different phenotypes. The
number of epitopes recognized, rather than recognition of specific epitopes, might be more
predictive of clinical features of food allergy.15 However, the overlap in the number of
epitopes recognized in different clinical group does not allow its clinical use.51,72,73,116–122
Oral Food Challenges

OFC are the key to establishing the identity of specific food triggers. The most rigorous
method is double-blinded and placebo-controlled (DBPC), but single-blind (patient) and
open challenges can be performed. The least time-intensive procedure is the open challenge.
With a previous history of anaphylaxis they are not needed, and they can be very dangerous
if history and allergy evaluation are concordant. OFC may be needed years after the
anaphylactic reaction has occurred in order to establish the possible development of
tolerance, especially in children. In such highly selected cases, they should be performed in
the hospital setting with an intensive care unit readily available, and should be started from
allergen doses of less than 100 mg of protein.123
TREATMENT
Epinephrine
Intramuscular injection of epinephrine into the vastus lateralis muscle (lateral thigh) is the
life-saving treatment in cases of FIA as well as for all types of anaphylactic reactions. All
other treatments such as antihistamines, glucocorticoids, and β-agonists, either alone or in
combination, are to be considered ancillary in the treatment of anaphylaxis.
In animal models and in humans, injected epinephrine rapidly reverses anaphylaxis, because
is an agonist for the adrenergic receptors (α-1, β-1, β-2).3,67–69,101,103,114,124 In humans,
prospective controlled studies on the use of epinephrine during an acute anaphylactic event
have not been done, for obvious ethical reasons; however, retrospective studies have shown
convincingly that lack of treatment with epinephrine within a few minutes of the beginning
of the symptoms is one of the major risk factors for death from FIA.
There is wide agreement that the optimal method of administration of epinephrine is

intramuscular, as subcutaneous injection can lead to local vasoconstriction with possible
delayed absorption, and decreased peak levels, while the intravenous route lacks an
established dosing regimen, is prone to dosing errors, is difficult to perform rapidly, and can
induce lethal arrhythmias.
In cases of profound hypotension or failure to respond to intramuscular epinephrine,

intraventricular epinephrine should be used while patients have continuous cardiac
monitoring in place.15,23,48,70,115,120,121,125
The recommended dose for intramuscular epinephrine injection 1:1000 solution (1 mg/mL)
is from 0.01 mg/kg to a maximum of 0.3 mg in children and 0.5 mg in adults. Commercially
available prefilled syringes for autoinjection are available in strengths of 0.15 and 0.3 mg.
The most recent guidelines from the NIH recommend switching to the 0.3-mg dose at
approximately 25 kg (55 lbs) because of the risk of underdosing above this weight if the
smaller dosage is used, even if the package instruction recommends the switch at 30 kg. For
children who have asthma or other additional risk factors for fatality from anaphylaxis,
switching to the higher dose at a lower weight might be considered. The same guidelines
recommend the use of the 0.15-mg auto-injector for patients weighing down to 10 kg. In
practice, self-injected epinephrine is prescribed even to smaller otherwise healthy infants,
because the risks of overdose with autoinjector use is weighed against the demonstrated
difficulty encountered by professionals and nonprofessionals with correctly and promptly
drawing up a correct-for-age dose of epinephrine into the syringe. The dose may be repeated
at intervals of at least 5 minutes if necessary. World Health Organization (WHO) and
Anaphylaxis Canada recommend the availability of 1 dose for every 10 to 20 minutes of
travel time to a medical emergency facility, and most guidelines recommend the prescription
of 2 doses, as in some cases of anaphylaxis one dose may not be
enough.15,23,48,70,115,120,121,125
Ideally epinephrine autoinjectors are prescribed on discharge from the emergency room after
management of anaphylaxis, or following consultation with a pediatrician or pediatric
allergist for suspected food allergy. Despite universal recommendations for the use of
epinephrine in anaphylaxis, it is actually uncommonly used in home or emergency room
treatment of FIA, and most patients with a history of anaphylaxis will discontinue its use
within a few years of the anaphylactic episode, perhaps because patients perceive
epinephrine as a dangerous medication or patients and practitioners do not think their
symptoms are severe enough to merit epinephrine.68,114,126 In general, it is recommended
that epinephrine be given to food-allergic children at the first signs of a systemic reaction,
before life-threatening symptoms such as respiratory distress and hypotension develop, as
those symptoms may be harder to reverse and may cause permanent damage to the subjects
(cerebral hypoxia). Patient with history of life-threatening reaction have to be instructed to
recognize the early symptoms of anaphylaxis (Box 5).
Box 5
Early symptoms of anaphylaxis
Itch of scalp, palms of hands, or soles of feet extending to acoustic meatus, lips, genital
area
Diffuse erythema
Oral or pharyngeal itch
Nasal congestion
Subjective sensation of throat tightness
Changes in the tone of voice: hoarseness
Swelling of lips and tongue
H1 Antihistamines
H1 antihistamines are inverse agonists at the H1 histamine receptor in that that they bind the
receptor in its inactive state, preventing signaling through the receptor. H1 antihistamines
are the most commonly used medications in the treatment of anaphylactic episodes both in
the hospital and outpatient setting. Although H1 antihistamines decrease skin symptoms
(itch, flush, urticaria) and nasal symptoms (rhinorrhea, congestion), they do not prevent or
treat life-threatening manifestations of anaphylaxis such as airway obstruction, wheeze, or

hypotension. Hence they are considered secondary medications for the treatment of
anaphylaxis, and their use in the outpatient setting is controversial. Indeed, even if the most
recent practice parameter suggests that they may have utility for “control of cutaneous and
cardiovascular manifestations” of anaphylaxis, others recommend against their use because
of their potential for both delaying life-saving therapy and causing dangerous side effects
such sedation (which could make assessment of the progression of anaphylaxis difficult),
neurotoxicity such as seizure, and potentially fatal QT prolongation. If antihistamines are
used for children, the dose should be 1 mg/kg up to 50 mg, whereas for adults the dose is 25
to 50 mg, whether given intramuscularly, intraventricularly, or by mouth.3,68,114
H2 Antihistamines
Like H1 antihistamines, H2 antihistamines are inverse agonists that preferentially bind to the
inactive state of the receptor. The H2 receptor participates in the anaphylactic response, and
even if theoretically blockade of this receptor may have an additive effect with the H1
antihistamines, their efficacy has been only suggested and not proved in cases of any kind of
anaphylaxis including FIA. The most recent United States practice parameter for
anaphylaxis states “an H2 antagonist added to the H1 antagonist may be helpful in the
management of anaphylaxis.” If used, ranitidine can be given intraventricularly or
intramuscularly at 1 mg/kg in children and 12.5 to 50 mg in adults. Infusion of cimetidine
should be done slowly to prevent hypotension.3,68,114
Glucocorticoids
Like antihistamines, the efficacy of glucocorticoids in the treatment of anaphylaxis has not
been proved in a randomized, double-blind, placebo-controlled trial, but is widely used in
the emergency room and outpatient settings. The onset of action of glucocorticoids is slow,
occurring hours after administration, and it is well known that pretreatment for 48 hours
with glucocorticoids prevents the late-phase response to allergen challenge; it does not affect
the acute-phase response. Glucocorticoids can cause significant adverse events if used long
term, but short-term use is generally much safer and mostly limited to mood changes,
increase in peripheral blood concentration of glucose, and occasional high blood pressure.
Their use may reduce the biphasic reaction but, given the rarity of such reactions, a double-
blind placebo-controlled study to prove such an effect is difficult to realize.3,68,114
β-Agonists
β-Agonists may be used as an adjunct to epinephrine for the treatment of wheeze, but should
not replace epinephrine because they lack the widespread effects of epinephrine and do not
effectively treat angioedema.3,68,114
Others
β-Blockers are associated with anaphylaxis that is difficult to treat in adults. If the patient is
taking β-blockers, glucagon can be useful.
Additional potentially life-saving supportive measures include placing the patient in a supine
position to maximize cardiac return, administering oxygen if needed, and giving
intraventricular fluids if hypotension develops.3,68,114
PREVENTION OF ANAPHYLAXIS AND FATAL ANAPHYLAXIS

Until recently the only proven prevention strategy for FIA has been food elimination in
subjects with a history of food allergy to a specific food. To facilitate allergen avoidance in
the United States the Food Allergen Labeling and Consumer Protection Act was enacted in
2005 to publish help on food labels to prevent accidental exposure to foods for the 8 most
common food allergens (milk, egg, peanut, tree nuts, fish, shellfish, soy, and wheat). Similar
legislation has been introduced in Japan, Europe, and Australia. All patients at risk for
anaphylaxis must be trained to identify relevant food allergens on the labels, and written
instruction should be given.115,124
Even if a correct diagnosis is made, accidental exposure and recurrence of anaphylaxis

induced by the same or different foods are frequent in subjects with FIA. Indeed most
patients who died of anaphylaxis knew they were allergic to the food that eventually killed
them.67–69,126 All patients with a history of anaphylaxis or at high risk of anaphylaxis
should be taught to recognize early symptoms (see Box 5) and be taught the use of
autoinjectable epinephrine with written and verbal instruction immediately after the
diagnosis of anaphylaxis is made. All patients at risk of anaphylaxis should leave the
clinician’s office or the hospital with a written plan indicating clearly the food allergies, the
dose of epinephrine to be used, and symptoms that should induce epinephrine use.1,3
In a recent report, Pumphrey and Gowland68 noted that more than half FIA-related deaths
occurred in patients whose previous reactions had been so mild that it was unlikely that a
doctor would have recommended they should carry self-injectable epinephrine. Indeed
recent NIH guidelines for food allergy management encourage clinicians to consider
prescribing an epinephrine autoinjector for all patients with food allergy having IgE-
mediated reactions, based on the fact that it is impossible to predict the severity of any
subsequent reactions with accuracy (Box 6)45 WHO and Anaphylaxis Canada recommend
the availability of 1 dose for every 10 to 20 minutes of travel time to a medical emergency
facility.
Box 6
Epinephrine autoinjector (or 2-dose prescription) NIH food allergy
guidelines 2010
All patients experiencing anaphylaxis should be provided directly with an epinephrine
autoinjector or, if this is not possible, with a prescription (recommended prescription is
for 2 doses of epinephrine), and advised to fill it immediately.
Other patients who should be prescribed an epinephrine autoinjector include:
1. Patients with a history of a prior systemic allergic reaction
2. Patients with food allergy and asthma
3. Patients with a known food allergy to peanut, tree nuts, fish, and crustacean
shellfish (ie, allergens known to be associated with more fatal and near-fatal
allergic reactions)
4. In addition, consideration should be given to prescribing an epinephrine
autoinjector for all patients with food allergy having IgE-mediated reactions
because it is impossible to predict the severity of any subsequent reactions with
accuracy
Data from Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and
management of food allergy in the United States: report of the NIAID-sponsored expert
panel. J Allergy Clin Immunol 2010;126(Suppl 6):S1–58.
More recently oral immunotherapy has been proved to be effective in the short term in
preventing anaphylaxis attributable to several foods such as milk, hazelnut, and eggs.127
Moreover, a unique combination of Chinese herbs, Zhi Fu Zi (Radix Lateralis Aconiti

Carmichaeli Praeparata) and Xi Xin (Herba Asari), could also help with the induction of
tolerance.127
FOOD-DEPENDENT EXERCISE-INDUCED ANAPHYLAXIS

Exercise-induced anaphylaxis (EIA) is a particular type of anaphylaxis that occurs while
performing intense exercise. It is estimated that 5% to 15% of anaphylactic episodes are
caused by or are associated with exercise. EIA may occur independently of food ingestion
(pure EIA) or in close time relationship with food ingestion (30% to 50% of EIA).128 Food-
dependent exercise-induced anaphylaxis (FDEIA) is diagnosed when anaphylactic episodes
occur only when exercise follows food ingestion (up to 6 hours, usually within 1–3 hours),
and is otherwise well tolerated. The most common foods reported in adults with FDEIA
include crustacean shellfish, celery, cheese, tomatoes, and alcohol. In adults with FDEIA
about 75% are female. Fifty percent report seasonal allergic rhinitis and 19% report
asthma.129 In children, FDEIA may be more frequent in teenage males and in association
with wheat allergy.130 Water-insoluble omega-5-gliadin (Tri a 19) has been identified as a
major allergen in Finnish subjects with FDEIA.40,41 However, a long list of foods including
many vegetables (ie, celery), cereals, milk, eggs, and meat has been reported as a cause of
FDEIA.14,131,132 Clinical presentations of FDEIA include pruritus, urticaria, angioedema,
flushing, shortness of breath, dysphagia, chest tightness, syncope, profuse sweating,
headache, nausea, diarrhea, colicky abdominal pain, throat closing, and hoarseness.128
FDEIA can manifest in teen years or adulthood in subjects without any prior history of food
allergy. In patients with suspected FDEIA, SPT to foods ingested prior to the exercise can
identify the offending food, although negative allergy test results do not rule out FDEIA.
Suspected FDEIA is one of the few situations for which a large panel of food skin tests
needs to be performed if the meal eaten before the exercise included many ingredients. A
food challenge followed by exercise on a treadmill may be necessary to confirm the
diagnosis in selected cases. Food challenges in FDEIA are a high-risk procedure, as the dose
of food and intensity of exercise required to induce a reaction cannot be well controlled, and
severe anaphylactic reactions have been reported.133 A positive challenge provides
definitive diagnosis. However, a negative challenge does not rule out FDEIA because the
intensity of exercise might have not been well reproduced, or because of the potential
necessary association of additional cofactors, such as pollen exposure or concomitant
ingestions of drugs such as nonsteroidal anti-inflammatory drugs or, in women, the
concomitant presence of menses.133 Management of FDEIA includes prompt treatment with
epinephrine during an acute episode.
To prevent FDEIA, the following strategies are recommended: (1) avoidance of exercise
within 4 to 6 hours following the incriminated food ingestion; (2) avoidance of exercising
alone or in hot or humid weather or during pollen allergy season; and (3) carrying
emergency medications. Patients with FDEIA often have environmental allergies to pollens,
and one of the major challenges is to distinguish between FDEIA and exercise-induced
asthma especially in those subjects in whom FDEIA is associated with dyspnea or wheezing.
Elevated serum tryptase levels have been reported in subjects with FDEIA following an
acute episode, and can be helpful in determining the diagnosis.128
SUMMARY
FIA is a serious allergic reaction that may cause death rapidly in otherwise healthy
individuals. There is no universal agreement on its definition or criteria for diagnosis.
Food is one of the most common causes of anaphylaxis, with most surveys indicating that
food-induced reactions account for 30% to 50% of anaphylaxis cases in North America,
Europe, Asia, and Australia, with up to 81% of anaphylaxis occurring in children.
Although a wide range of foods has been reported as a cause of FIA, the most commonly
implicated foods worldwide are peanut, tree nuts, milk, egg, sesame seeds, fish, and
shellfish, in both adults and children.
Allergens and patients’ characteristics are probably important in determining an

anaphylactic reaction. The major risk factor for FIA appears to be food allergy, in particular
for those with asthma with allergy to peanut, tree nuts, and shellfish, adolescents, and young
adults. The severity of previous allergic reaction is not predictive of the severity of any
future allergic reaction. The only life-saving treatment for anaphylaxis is allergen avoidance
and intramuscular epinephrine injection if an anaphylactic event occurs. All patients at risk
for FIA should be provided with an anaphylaxis plan that indicates allergen and treatment
modalities, as well as with self-injectable epinephrine.
Acknowledgments
Funding sources: NIH K08 AI089982-01A1.
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NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Table 1
Most common cause of FIA
Food Type of Anaphylaxis % Country Refs. Age Food Type of Anaphylaxis % Country Refs. Age
Peanut Fatal 42 Australia 38 Peds and adults Egg Fatal 2 UK 68 Peds and adults
62 USA 69 Peds and adults ED/Hospital 9 Australia 38 Peds and adults

67 70
Cianferoni and Muraro
53 USA Peds and adults 9 Israel Peds
19 UK 68 Peds and adults 2 USA 48 Peds
ED/Hospital 23 Australia 38 Peds and adults Registry 7 Germany 47 Peds
0 Israel 70 Peds Allergy office 11 Italy 71 Peds
10 Italy 23 Adults 7 Spain 28 Peds
22 USA 48 Peds 0 Italy 29 Adults
Registry 22 Germany 47 Peds Vegetables Fatal 2 UK 68 Peds and adults
Allergy office 0 Italy 71 Peds ED/Hospital
0 Spain 28 Peds Registry 10 47 Peds
3 Italy 29 Adults Allergy office 4 Italy 71
Tree nuts Fatal 28 USA 69 Peds and adults 3 Italy 29 Adults
25 USA 67 Peds and adults Fruit Fatal/near fatal
19 UK 68 Peds and adults ED/Hospital 13 Israel 70 Peds
ED/Hospital 16 Australia 38 Peds and adults 8 USA 48 Peds
23 Israel 70 Peds Registry 4 Germany 47 Peds
18 USA 48 Peds Allergy office 11 Italy 71 Peds
Registry 25 Germany 47 Peds 8 Spain 28 Peds
Allergy office 13 Italy 71 Peds 31 Italy 29 Adults
16 Spain 28 Peds Cereal Fatal/near fatal
19 Italy 29 Adults ED/Hospital
Fish Fatal 14 Australia 38 Peds and adults Registry 2 Germany 47 Peds
Shellfish 3 USA 69 Peds and adults Allergy office 5 Italy 71 Peds
6 USA 67 Peds and adults 5 Italy 29 Adults

Page 24
Food Type of Anaphylaxis % Country Refs. Age Food Type of Anaphylaxis % Country Refs. Age
4 UK 68 Peds and adults Soy Fatal/near fatal
ED/Hospital 34 Australia 38 Peds and adults ED/Hospital 4.5 Israel 70 Peds
30 Italy 23 Adults 10 Italy 23 Adults
5 USA 48 Peds Registry 1 Germany 47 Peds
Registry 5 Germany 47 Peds Allergy office

Allergy office 30 Italy 71 Peds
22 Spain 28 Peds
18 Italy 29 Adults
Milk Fatal 3 USA 69 Peds and adults
12 USA 67 Peds and adults
12 UK 68 Peds and adults
ED/Hospital 8 Australia 38 Peds and adults
39 Israel 70 Peds
0 Italy 23 Adults
18 USA 48 Peds
Registry 9 Germany 47 Peds
Allergy office 22 Italy 71 Peds
47 Spain 28 Peds
0 Italy 29 Adults
Abbreviations: ED, emergency department; Peds, pediatric patients.
Page 25
Table 2a
Allergen described in egg, cow’s milk, soy, peanut
Allergen Name Allergen Common Name Clinical Relevance Allergen Name Allergen Common Name Clinical Relevance
Hen’s egg (Gallus Peanut (Arachis hypogea)
domesticus)
Gal d 1 Ovomucoid Ara h 1 Seed storage proteins Heat stable
Gal d 2 Ovalbumin Major allergen Ara h 2 Seed storage proteins Heat stable, associated with
anaphylaxis
Gal d 3 Ovotransferrin/conalbumin Ara h 3 Seed storage proteins
Gal d 4 Lysozyme Ara h 4 Seed storage proteins
Gal d 5 α-Livetin Bird-egg syndrome Ara h 5 Profilin (Bet v 2 like) Cross-reactive with other
plants; little clinical
relevance
Cow’s milk Ara h 6 Seed storage proteins Homology with Ara h 2.

Allergy persists
Bos d 8 α−, α.2-n, β-, γ1, γ2 Major allergen, heat stable Ara h 7 Seed storage proteins
γs K-casein
Bos d 4 α-Lactalbumin Major allergen, heat sensitive Ara h 8 Bet v 1 family (PR-1 O, Bet v 1 Responsible for cross-
like) reactivity with birch pollen
analogues
Bos d 5 β-Lactoglobulin Major allergen, heat sensitive Ara h 9 LTP Low prevalence of
recognition in USA and
north Europe; more common
in south Europe
Bos d 7 Immunoglobulin Ara h 10 Oleosin plant lipid storage bodies
Bos d 6 BSA Cross-reactivity with beef Ara h 11 Oleosin plant lipid storage bodies
Soybean (Glycine max)
Gly m 1 LTP
Gly m 2 Defensin
Gly m 3 Profilin
Gly m 4 Bet v 1 family (PR-1 O, Bet v 1 Cross-reactive with birch/

like) peanut, mild oropharyngeal
reaction
Gly m 5 Vicilin Severe reaction
Gly m 6 Legumin Severe reaction
Abbreviations: BSA, bovine serum albumin; LTP, lipid transfer protein.

Page 26
Table 2b
Allergens described in legumes, tree nuts, and seeds
Allergen Name Allergen Common Name Clinical Relevance Allergen Name Allergen Common Name Clinical Relevance
Pea (Pisum sativum) Sesame
Pis s 1 Vicilin Ses i 1 S albumin
Pis s 2 Convicilin Ses i 2 S albumin

Green bean (Phaseolus vu/garis) Ses i 3 7S globulin
Pha v 3 nsLTP type 1 Ses i 4 Oleosin
Hazelnut (Corylus avellana) Ses i 5 Oleosin
Cor a 1 PR-10 (Bet v 1 homologous) Ses i 6 Basic subunit of 11S globulins
Cor a 2 Profilin Ses i 7 Basic subunit of 11S globulins
Cor a 8 PR-14 (LPT) 9 Lupine (Lupinus angustifolius)
Cor a 9 Globulin (11S) Lup an 1 β-Conglutin (vicilin)
Cor a 11 Vicilin (7S) Lentil (Lens culinaris)
Chestnut (Castanea sativa) Len c 1 γ-Vicilin subunit
Cas s 5 Chitinase Ib Len c 2 Seed specific
Cas s 8 PR-14 (LPT) Oral allergy syndrome Len c 3 nsLTP type 1
Brazil nut Cashew (Anacardium occidentale)
Ber e 1 Albumin (2S) Anaphylaxis Ana o 1 Vicilin (7S)
Ber e 2 Legumin (11S) Anaphylaxis Ana o 2 Legumin (11S)
Walnut (Juglans regia)
Jug r 1 Albumin (2S)
Jug r 2 Vicilin (7S)
Jug r 3 PR-14 (LTP)
Jug r 4 Legumin (11S)
Page 27
Table 2c
Allergens in seafood
Allergen Name Allergen Common Name Clinical Relevance

Fish
Baltic cod (Gadus callarias), Atlantic

cod (Gadus morhua), Atlantic salmon
(Salmo salar), edible frog (Rana
esculenta)
Gad c 1 Parvalbumin Anaphylaxis cross-reactivity among multiple fish

Gad m 1
Sal s 1
Ran e 1
Shellfish
Greasyback shrimp (Metapenaeus

ensis), brown shrimp (Penaeus aztecus),
black tiger shrimp (Penaeus monodon),
shrimp (Penaeus indicus), Crab
(Charybdis feriatus), lobster (Homarus
americanus, Panulirus stimpsoni), squid

(Todarodes pacificus), Snail (Helix
aspera), abalone (Haliotis midae)
Met e 1 Tropomyosin Anaphylaxis cross-reaction with multiple shellfish and with

house dust mite
Pen a 1
Pen m 1
Pen i 1
Cha f 1
Hom a 1
Pan s 1
Tod p 1
Hel as 1
Hal m 1
Shrimp (Penaeus indicus)
Myosin light chain Anaphylaxis

Black tiger shrimp (Penaeus monodon),

shrimp (Penaeus indicus)
Sarcoplasmic calcium- binding

protein
Black tiger shrimp (Penaeus monodon)
Table 3
Family of most common allergenic foods: peanut, tree nuts, and seafood
Common Cause of Uncommon Cause of

Family Species Common Name Anaphylaxis Anaphylaxis
Leguminoseae Arachis hypogea Peanut +
Betulaceae Corylus avellana Hazelnut +
Anacardiaceae Anacardium occidentale Cashew +
Pistacia vera Pistachio +
Juglandaceae Juglans regia Walnut +
Carya illinoinensis Pecan nut +
Rosaceae Prunus dulcis Almond +
Lecythidaceae Bertholletia excelsa Brazil nut +
Fagaceae Castanea sativa Chestnut +
Pinaceae Pinus pinea Pine nut +
Proteaceae Macadamia intergrifolia Macadamia nut +
Palmaceae Cocos nucifera Coconut +

Arthropods Crustaceans Crab, rock lobster, prawn, shrimp +

Shellfish
Mollusks Gastropods Abalone, snail, whelk +
Bivalves Clam, oyster, scallop, mussel, cockles +
Cephalopods Squid (cuttlefish), octopus +
Chordate Teleosts Tuna, salmon, carp, trout + +
Data from Lopata AL, O’Hehir RE, Lehrer SB. Shellfish allergy. Clin Exp Allergy 2010;40(6):850–8; and Crespo JF, James JM, Fernandez-
Rodriguez C, et al. Food allergy: nuts and tree nuts. British J Nutr 2006;96(Suppl 2):S95–102.
Table 4
Mediators involved in anaphylaxis
Mediators Effects Clinical Manifestation

Histamine Agonist of H1 and H2 receptors, which causes Urticaria, angioedema, asthma,
increase in the vascular permeability, vasodilation, hypotension, abdominal cramps, diarrhea
contraction of smooth muscle cells, increase in
exocrine gland secretion, and irritation of sensory
nerves
Lipooxygenase pathway products Chemotaxis Biphasic reaction, asthma, hypotension

Contraction of smooth muscle cells, increase in
LTB4 vascular permeability, increase in exocrine gland
secretion (goblet cells)
LTC4
LTD4
Cyclooxygenase Vasodilation, contraction of smooth muscle cells, Asthma, hypotension, heart ischemia
coronary vasoconstriction, increase in exocrine gland
PGD2 secretion (goblet cells)
PGF2a
TXA2
PAF Induction of arachidonic acid metabolites Asthma, hypotension
Chemotactic factors for eosinophils Tissue infiltration and activation of eosinophils and Possible role in biphasic or prolonged
and neutrophils neutrophils reactions
Tryptase Activates complement through C3 No clear physiologic role

Cut fibrinogen
Activates kallikrein
Kininogenase of mast cells and Activation of contact system, release of kinins No clear physiologic role
basophil kallikrein
Chymase Degrades neuropeptides Hypotension and inhibition of

Conversion of angiotensin I to II neuropeptides
Heparin Inhibition of coagulation, plasmin, kallikrein and Possible anti-inflammatory role

complement
Abbreviations: LTB, leukotriene B; LTC, leukotriene C; LTD, leukotriene D; PAF, platelet-activating factor; PGD, prostaglandin D; PGF,
prostaglandin F; TXA, thromboxane A.
Table 5
Adverse reactions to seafood generated by different triggers
Symptoms Time of Reaction
Bacteria
Aeromonas, Listeria, Salmonella, Vibrio, Klebsiella Cutaneous, gastrointestinal, and neurologic Minutes to several hours
pneumoniae, Proteus morganii (headache)
Viruses
Rotavirus, astrovirus, hepatitis A, small round viruses, etc Gastrointestinal Hours
Parasites
Anisakis Respiratory distress Minutes to several hours
Toxins
Algae toxins

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NIH Public Access: Food-Induced Anaphylaxis

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© 2012 Elsevier Inc. All rights reserved.

3. Hypotension after exposure to known allergen for that patient (minutes to

to 1 year [<70 mm Hg + (2 × age)] from 1 to 10 years, and <90 mm Hg from 11 to 17

Based on this latest recommendation,1,3 FIA is diagnosed when

5. Limited ability of International Classification of Diseases (ICD) 995.6 code

hospitalization, emergency room visits, epinephrine prescription, and ambulance transport

Peanut/tree nuts anaphylaxis is estimated to have a prevalence of 0.25% to 0.95% in the

Reports of anaphylaxis in exclusively breast-fed babies due to passage of food allergens

The spectrum of foods responsible for causing anaphylaxis appears to be broadening, to

elevated food-specific serum IgE. Anaphylaxis was reported by 5% of food-allergic

gal), is capable of eliciting delayed systemic symptoms of anaphylaxis,

Peanut/Tree Nut Anaphylaxis

Assessment of cross-reactivity among tree nuts is complicated by shared allergens among

Milk, Egg, and Soy

d. Medullary and thyroid carcinoma

b. Anaphylaxis due to progesterone

Cardiac enzymes → cardiac ischemia?

however, individual results do not provide prognostic information or distinguish between

Oral Food Challenges

There is wide agreement that the optimal method of administration of epinephrine is

In cases of profound hypotension or failure to respond to intramuscular epinephrine,

treat life-threatening manifestations of anaphylaxis such as airway obstruction, wheeze, or

PREVENTION OF ANAPHYLAXIS AND FATAL ANAPHYLAXIS

Even if a correct diagnosis is made, accidental exposure and recurrence of anaphylaxis

Moreover, a unique combination of Chinese herbs, Zhi Fu Zi (Radix Lateralis Aconiti

FOOD-DEPENDENT EXERCISE-INDUCED ANAPHYLAXIS

Allergens and patients’ characteristics are probably important in determining an

features. Pediatrics. 1998; 101(4):E8. [PubMed: 9521974]

reactions on challenges. Ann Allergy Asthma Immunol. 2004; 92(2):217–24. [PubMed:

Th2 adjuvant in vitro. J Immunol. 2006; 177(6):3677–85. [PubMed: 16951327]

Ann Allergy Asthma Immunol. 2004; 92(4):464–8. [PubMed: 15104200]

62 USA 69 Peds and adults ED/Hospital 9 Australia 38 Peds and adults

53 USA Peds and adults 9 Israel Peds

19 UK 68 Peds and adults 2 USA 48 Peds

ED/Hospital 23 Australia 38 Peds and adults Registry 7 Germany 47 Peds

0 Israel 70 Peds Allergy office 11 Italy 71 Peds

10 Italy 23 Adults 7 Spain 28 Peds

22 USA 48 Peds 0 Italy 29 Adults

Registry 22 Germany 47 Peds Vegetables Fatal 2 UK 68 Peds and adults

Allergy office 0 Italy 71 Peds ED/Hospital

0 Spain 28 Peds Registry 10 47 Peds

3 Italy 29 Adults Allergy office 4 Italy 71

Tree nuts Fatal 28 USA 69 Peds and adults 3 Italy 29 Adults

25 USA 67 Peds and adults Fruit Fatal/near fatal

19 UK 68 Peds and adults ED/Hospital 13 Israel 70 Peds

ED/Hospital 16 Australia 38 Peds and adults 8 USA 48 Peds

23 Israel 70 Peds Registry 4 Germany 47 Peds

18 USA 48 Peds Allergy office 11 Italy 71 Peds

Registry 25 Germany 47 Peds 8 Spain 28 Peds

Allergy office 13 Italy 71 Peds 31 Italy 29 Adults

19 Italy 29 Adults ED/Hospital

Fish Fatal 14 Australia 38 Peds and adults Registry 2 Germany 47 Peds

Shellfish 3 USA 69 Peds and adults Allergy office 5 Italy 71 Peds

6 USA 67 Peds and adults 5 Italy 29 Adults

ED/Hospital 34 Australia 38 Peds and adults ED/Hospital 4.5 Israel 70 Peds

30 Italy 23 Adults 10 Italy 23 Adults

5 USA 48 Peds Registry 1 Germany 47 Peds

Registry 5 Germany 47 Peds Allergy office

Allergy office 30 Italy 71 Peds

Milk Fatal 3 USA 69 Peds and adults

12 USA 67 Peds and adults

12 UK 68 Peds and adults